TIAGABINE THERAPEUTICS Brands Gabitril see index for additional brand names Generic? Yes Class Anticonvulsant; selective GABA reuptake inhibitor (SGRI) Commonly Prescribed for (bold for FDA approved) Partial seizures (adjunctive; adults and children 12 years and older) Anxiety disorders Neuropathic pain/chronic pain How the Drug Works Selectively blocks reuptake of gammaaminobutyric acid (GABA) by presynaptic and glial GABA transporters How Long Until It Works Should reduce seizures by 2 weeks Not clear that it works in anxiety disorders or chronic pain but some patients may respond, and if they do, therapeutic actions can be seen by 2 weeks If It Works The goal of treatment is complete remission of symptoms (e.g., seizures, anxiety) The goal of treatment of chronic neuropathic pain is to reduce symptoms as much as possible, especially in combination with other treatments Treatment of chronic neuropathic pain most often reduces but does not eliminate symptoms and is not a cure since symptoms usually recur after medicine stopped Continue treatment until all symptoms are gone or until improvement is stable and then continue treating indefi nitely as long as improvement persists If It Doesn t Work (for neuropathic pain or anxiety disorders) Many patients have only a partial response where some symptoms are improved but others persist Other patients may be nonresponders, sometimes called treatment-resistant or treatment-refractory May only be effective in a subset of patients with neuropathic pain or anxiety disorders, in some patients who fail to respond to other treatments, or it may not work at all Consider increasing dose, switching to another agent or adding an appropriate augmenting agent Consider biofeedback or hypnosis for pain Consider evaluation for another diagnosis or for a comorbid condition (e.g., medical illness, substance abuse, etc.) Switch to another agent with fewer side effects Best Augmenting Combos for Partial Response or Treatment Resistance Tiagabine is itself an augmenting agent for numerous other anticonvulsants in treating For neuropathic pain, tiagabine can augment TCAs and SNRIs as well as gabapentin, other anticonvulsants, and even opiates if done by experts while carefully monitoring in diffi cult cases For anxiety, tiagabine is a second-line treatment to augment SSRIs, SNRIs, or benzodiazepines Tests None for healthy individuals Tiagabine may bind to tissue that contains melanin, so for long-term treatment opthalmological checks may be considered SIDE EFFECTS How Drug Causes Side Effects CNS side effects may be due to excessive actions of GABA Notable Side Effects Sedation, dizziness, asthenia, nervousness, diffi culty concentrating, speech/language problems, confusion, tremor Diarrhea, vomiting, nausea Ecchymosis, depression 719
TIAGABINE (continued) Life-Threatening or Dangerous Side Effects Exacerbation of EEG abnormalities in Status epilepticus in (unknown if associated with tiagabine use) Sudden unexplained deaths have occurred in (unknown if related to tiagabine use) New onset seizures and status epilepticus have been reported in patients without Rare activation of suicidal ideation and behavior (suicidality) Weight Gain Reported but not expected Some patients experience increased appetite Sedation Many experience and/or can be signifi cant in amount What To do About Side Effects Take more of the dose at night or all of the dose at night to reduce daytime sedation Lower the dose Switch to another agent Best Augmenting Agents for Side Effects Many side effects cannot be improved with an augmenting agent DOSING AND USE Usual Dosage Range 32 56 mg/day in 2 4 divided doses for adjunctive treatment of 2 12 mg/day for adjunctive treatment of chronic pain and anxiety disorders Dosage Forms Tablet 2 mg, 4 mg, 12 mg, 16 mg, 20 mg How To Dose Adjunct to enzyme-inducing antiepileptic drugs: initial 4 mg once daily; after 1 week can increase dose by 4 8 mg/day each week; maximum dose generally 56 mg/day in 2 4 divided doses Dosing for chronic pain or anxiety disorders not well established, but start as low as 2 mg at night, increasing by 2 mg increments every few days as tolerated to 8 12 mg/day Exercise particular caution when prescribing in uninduced patients Dosing Tips Usually administered as adjunctive medication to other anticonvulsants in the treatment of Dosing recommendations are based on studies of adjunctive use with enzymeinducing antiepileptic drugs, which lower plasma levels of tiagabine by half; thus, when tiagabine is used without enzymeinducing antiepileptic drugs the dose may need to be signifi cantly reduced and may require a much slower titration rate Also administered as adjunctive medication to benzodiazepines, SSRIs, and/or SNRIs in the treatment of anxiety disorders; and to SNRIs, gabapentin, other anticonvulsants, and even opiates in the treatment of chronic pain Dosing varies considerably among individual patients but is defi nitely at the lower end of the dosing spectrum for patients with chronic neuropathic pain or anxiety disorders (i.e., 2 12 mg either as a split dose or all at night) Patients with chronic neuropathic pain and anxiety disorders are far less tolerant of CNS side effects, so they require a much slower dosage titration as well as a lower maintenance dose Gastrointestinal absorption is markedly slowed by the concomitant intake of food, which also lessens the peak plasma concentrations Thus, for improved tolerability and consistent clinical actions, instruct patients to always take with food Side effects may increase with dose 720
(continued) TIAGABINE Overdose No fatalities have been reported; sedation, agitation, confusion, speech diffi culty, hostility, depression, weakness, myoclonus, seizures, status epilepticus Long-Term Use Safe Habit Forming No How to Stop Taper Epilepsy patients may seize upon withdrawal, especially if withdrawal is abrupt Discontinuation symptoms uncommon Pharmacokinetics Primarily metabolized by CYP450 3A4 Steady-state concentrations tend to be lower in the evening than in the morning Half-life approximately 7 9 hours Renally excreted Drug Interactions Clearance of tiagabine may be reduced and thus plasma levels increased if taken with a non-enzyme-inducing antiepileptic drug (e.g., valproate, gabapentin, lamotrigine), so tiagabine dose may need to be reduced CYP450 3A4 inducers such as carbamazepine can lower the plasma levels of tiagabine CYP450 3A4 inhibitors such as nefazodone, fl uvoxamine, and fl uoxetine could theoretically increase the plasma levels of tiagabine Clearance of tiagabine is increased if taken with an enzyme-inducing antiepileptic drug (e.g., carbamazepine, phenobarbital, phenytoin, primidone) and thus plasma levels are reduced ; however, no dose adjustments are necessary for treatment of as the dosing recommendations for are based on adjunctive treatment with an enzyme-inducing antiepileptic drug Despite common actions upon GABA, no pharmacodynamic or pharmacokinetic interations have been shown when tiagabine is combined with the benzodiazepine triazolam or with alcohol However, sedating actions of any two sedative drugs given in combination can be additive Other Warnings/ Precautions Seizures have occurred in individuals without who took tiagabine Risk of seizure may be dose-related; when tiagabine is used in the absence of enzymeinducing antiepileptic drugs, which lower plasma levels of tiagabine, the dose may need to be reduced Depressive effects may be increased by other CNS depressants (alcohol, MAOIs, other anticonvulsants, etc.) Tiagabine may bind to melanin, raising the possibility of long-term ophthalmologic effects Warn patients and their caregivers about the possibility of activation of suicidal ideation and advise them to report such side effects immediately Do Not Use If there is a proven allergy to tiagabine SPECIAL POPULATIONS Renal Impairment Although tiagabine is renally excreted, the pharmacokinetics of tiagabine in healthy patients and in those with impaired renal function are similar and no dose adjustment is recommended Hepatic Impairment Clearance is decreased May require lower dose Cardiac Impairment No dose adjustment recommended Elderly Some patients may tolerate lower doses better Children and Adolescents Safety and effi cacy not established in children under age 12 Maximum recommended dose generally 32 mg/day in 2 4 divided doses 721
TIAGABINE (continued) Pregnancy Effective June 30, 2015, the US FDA requires changes to the content and format of pregnancy and lactation information in prescription drug labels, including the elimination of the pregnancy letter categories; the Pregnancy and Lactation Labeling Rule (PLLR or fi nal rule) applies only to prescription drugs and will be phased in gradually for drugs approved on or after June 30, 2001 Controlled studies have not been conducted in pregnant women Use in women of childbearing potential requires weighing potential benefi ts to the mother against the risks to the fetus Antiepileptic Drug Pregnancy Registry: (888) 233 2334 Taper drug if discontinuing Seizures, even mild seizures, may cause harm to the embryo/fetus Lack of defi nitive evidence of effi cacy for chronic neuropathic pain or anxiety disorders suggests risk/benefi t ratio is in favor of discontinuing tiagabine during pregnancy for those indications Breast Feeding Some drug is found in mother s breast milk Recommended either to discontinue drug or bottle feed If drug is continued while breast feeding, infant should be monitored for possible adverse effects If infant shows signs of irritability or sedation, drug may need to be discontinued THE ART OF PSYCHOPHARMACOLOGY Potential Advantages Treatment-resistant chronic neuropathic pain Treatment-resistant anxiety disorders Potential Disadvantages May require 2 4 times a day dosing Needs to be taken with food Primary Target Symptoms Incidence of seizures Pain Anxiety Pearls Well studied in Much use is off label Off-label use second-line and as an augmenting agent may be justifi ed for treatment-resistant anxiety disorders and neuropathic pain and also for fi bromyalgia Off-label use for bipolar disorder may not be justifi ed One of the few agents that enhances slow-wave delta sleep, which may be helpful in chronic neuropathic pain syndromes Can be diffi cult to dose in patients who are not taking enzyme-inducing anticonvulsant drugs as the doses in uninduced patients have not been well studied, are generally much lower, and titration is much slower than in induced patients Can cause seizures even in patients without, especially in patients taking other agents (antidepressants, antipsychotics, stimulants, narcotics) that are thought to lower the seizure threshold 722
(continued) TIAGABINE Suggested Reading Backonja NM. Use of anticonvulsants for treatment of neuropathic pain. Neurology 2002 10;59 (Suppl 2):S14 17. Carta MG, Hardoy MC, Grunze H, Carpiniello B. The use of tiagabine in affective disorders. Pharmacopsychiatry 2002 ;35:33 4. Evans EA. Effi cacy of newer anticonvulsant medications in bipolar spectrum mood disorders. J Clin Psychiatry 2003 ;64 (Suppl 8):S9 14. Lydiard RB. The role of GABA in anxiety disorders. J Clin Psychiatry 2003 ;64 (Suppl 3):S21 7. Schmidt D, Gram L, Brodie M, et al. Tiagabine in the treatment of a clinical review with a guide for the prescribing physician. Epilepsy Res 2000 ;41:245 51. Stahl SM. Anticonvulsants as anxiolytics, part 1: tiagabine and other anticonvulsants with actions on GABA. J Clin Psychiatry 2004 ;65:291 2. Stahl SM. Psychopharmacology of anticonvulsants: do all anticonvulsants have the same mechanism of action? J Clin Psychiatry 2004 ;65 :149 50. 723